Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines

The deletion of the short arm of chromosome 3 is frequently observed in lung cancer. To determine whether the von Hippel-Lindau (VHL) disease tumor suppressor gene located at 3p25 is responsible for oncogenesis in lung cancer, we searched the known open reading frame using the single-strand conformation polymorphism (SSCP) technique for mutations in the VHL gene in 72 cancer cell lines including small cell (SCLC) and non-small cell (NSCLC) lung cancers, carcinoids, and mesotheliomas. SSCP analysis showed that four cell lines have altered SSCP patterns within the coding region and one in an intron of the VHL gene. SCLC line NCI-H1672 had a somatic mutation, G to A at nucleotide (nt) 530, leading to amino acid substitution (glycine to aspartic acid) compared to normal DNA from the same patient. Mesothelioma line NCI-H28 had T to A mutation at nt 479 leading to leucine to histidine amino acid change. We found one frequent polymorphism A (0.72) or G (0.28) at nt 19 resulting in either serine or glycine at this position, changes also found in normal peripheral blood cell DNA, often in a heterozygous state. In addition, we found single rare polymorphisms which did not alter the coding region including: C to G at nt 396, G to T at nt 843, and C to T change in an intron. These results suggest that the VHL gene is only rarely mutated in thoracic malignancies.     

A training curriculum for professional psychologists in primary care.

Primary care psychology is a growing field that requires specific training opportunities for successful practice. The knowledge and skills that practitioners need for work in this setting are outlined here in detail. This curriculum integrates literature and experience in family psychology, health psychology, and pediatric psychology; considers multiple levels of education and training; and provides illustrative examples. It is a first attempt in an evolving process of integrating historical and cutting edge literature from many areas of psychology and other disciplines to contribute to comprehensive primary care psychology training. It can be used by programs and individual practitioners alike in designing education and training experiences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia

Matrix metalloproteinases (MPs) constitute a family of proteolytic enzymes (proteases) that degrade extracellular matrix (ECM) and promote the local or metastatic potential of carcinoma cells, and whose action is restrained by special inhibitors (metalloproteinase inhibitors; MIs). We assessed the role of the MPs stromelysin-3 (STR-3), putative metalloproteinase-1 (PUMP-I), and the gelatinases of molecular weights 72 kDa and 92 kDa, as well as the role of their inhibitors tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, as markers of metastatic potential in 25 fresh biopsies of squamous-cell lung carcinomas (SCLCs). We examined levels of messenger ribonucleic acid (mRNA) expression for these MPs and inhibitors through Northern blot analysis in 10 carcinomas of high-to-moderate differentiation without lymph-node involvement, and in 15 infiltrative carcinomas of moderate-to-low differentiation with lymph-node involvement. Five cases with significant epithelial atypia and five samples with normal mucosa were used as controls. Expression of STR-3 and TIMP-2 was also assessed immunohistochemically with the avidin-biotin-complex (ABC) technique. We noticed a progressive increase in the expression levels of MPs, especially of STR-3, and of TIMP-2, from the stage of epithelial atypia to the detection of carcinoma, finding the highest values of these substances among carcinomas of low differentiation with nodal metastases. These findings were also confirmed with immunohistochemical analysis. Our results suggest that there is a significant association of the expression of MPs and MIs with both the local and metastatic potential and the degree of cellular differentiation of SCLC, and that this association is clinically important because of its prognostic and therapeutic implications.     

Translating emerging research on the genetics of smoking into clinical practice: ethical and social considerations.

Despite decades of research aimed at improving the effectiveness of smoking treatment, available treatments are only modestly effective, and smoking remains the leading cause of preventable deaths in the United States. Recent research on genetic factors related to smoking behavior eventually may lead to the design of new tobacco dependence treatments and to the individualization of treatment based on genetic factors. Although this research is in its infancy, and data on the analytic and clinical validity of genetic tests to tailor smoking treatment are not yet available, it is not too soon to begin identifying and addressing key ethical issues associated with genetic testing in the context of tobacco dependence treatment. Key concerns include (a) potential harm (e.g., stigmatization, discrimination) to patients related to inappropriate use of genetic information, (b) implications of pleiotropic associations, (c) differential prevalence of risk-conferring genotypes among racial or ethnic subpopulations, (d) preparedness of primary care physicians to incorporate genetic testing into smoking treatment, (e) informed consent, and (f) ensuring an appropriate balance between individually tailored treatment by genotype and broad-based interventions that focus on social and environmental factors affecting smoking behavior. Additional research on these ethical and social issues must be conducted simultaneously with the scientific work currently under way. Failure to address these concerns will likely undermine efforts to translate knowledge emerging from the United States' substantial investment in genetic research on smoking into clinical practice and improved patient outcomes.     

NotI Microarrays: Novel Epigenetic Markers for Early Detection and Prognosis of High Grade Serous Ovarian Cancer

Chromosome 3-specific NotI microarray (NMA) containing 180 clones with 188 genes was used in the study to analyze 18 high grade serous ovarian cancer (HGSOC) samples and 7 benign ovarian tumors. We aimed to find novel methylation-dependent biomarkers for early detection and prognosis of HGSOC. Thirty five NotI markers showed frequency of methylation/deletion more or equal to 17%. To check the results of NMA hybridizations several samples for four genes (LRRC3B, THRB, ITGA9 and RBSP3 (CTDSPL)) were bisulfite sequenced and confirmed the results of NMA hybridization. A set of eight biomarkers: NKIRAS1/RPL15, THRB, RBPS3 (CTDSPL), IQSEC1, NBEAL2, ZIC4, LOC285205 and FOXP1, was identified as the most prominent set capable to detect both early and late stages of ovarian cancer. Sensitivity of this set is equal to (72 ± 11)% and specificity (94 ± 5)%. Early stages represented the most complicated cases for detection. To distinguish between Stages I + II and Stages III + IV of ovarian cancer the most perspective set of biomarkers would include LOC285205, CGGBP1, EPHB1 and NKIRAS1/RPL15. The sensitivity of the set is equal to (80 ± 13)% and the specificity is (88 ± 12)%. Using this technique we plan to validate this panel with new epithelial ovarian cancer samples and add markers from other chromosomes.     

Preparation of rhombus-shaped micro/nanofluidic channels with dimensions ranging from hundred nanometers to several micrometers

Nanofluidic devices are of great interest due to their promising applications in biological/chemical detection and miniaturized power supplies. A rhombus-shaped channel with nanometer-sized opening is of particular interest as it can induce versatile symmetry-breaking phenomena such as current gating and rectification, hysteresis, biomolecule stretching etc. However, existing nanofabrication techniques, such as electron beam lithography, are usually costly and time-consuming as the target pattern has a spectrum of characteristic dimensions varying from nanometers to micrometers. In this work, a rhombus-shaped micro/nanofluidic channel with lateral dimension as small as a few hundred nanometers was prepared by depositing SiO2 into a pre-etched microchannel. The low pressure chemical vapor deposition (LPCVD) guaranteed excellent step coverage during the deposition and a 2.1 microm-thick SiO2 filling shrank the original micrometer-sized opening down to 150 nm. By this etching-filling process, fluidic devices with feature size ranging from hundred nanometers to several micrometers can be fabricated as a single monolith, thereby facilitating the fabrication of composite micro/nanofluidics systems.     

On Constructing One-Way Permutations from Indistinguishability Obfuscation

We prove that there is no black-box construction of a one-way permutation family from a one-way function and an indistinguishability obfuscator for the class of all oracle-aided circuits, where the construction is “domain invariant” (i.e., where each permutation may have its own domain, but these domains are independent of the underlying building blocks). Following the framework of Asharov and Segev (FOCS ’15), by considering indistinguishability obfuscation for oracle-aided circuits we capture the common techniques that have been used so far in constructions based on indistinguishability obfuscation. These include, in particular, non-black-box techniques such as the punctured programming approach of Sahai and Waters (STOC ’14) and its variants, as well as sub-exponential security assumptions. For example, we fully capture the construction of a trapdoor permutation family from a one-way function and an indistinguishability obfuscator due to Bitansky, Paneth, and Wichs (TCC ’16). Their construction is not domain invariant, and our result shows that this, somewhat undesirable property, is unavoidable using the common techniques. In fact, we observe that constructions which are not domain invariant circumvent all known negative results for constructing one-way permutations based on one-way functions, starting with Rudich’s seminal work (PhD thesis ’88). We revisit this classic and fundamental problem and resolve this somewhat surprising gap by ruling out all such black-box constructions—even those that are not domain invariant.     

Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial.

This study examined the role of dopaminergic genes in prospective smoking cessation and response to bupropion treatment in a placebo-controlled clinical trial. Smokers of European ancestry (N=418) provided blood samples for genetic analysis and received either bupropion or placebo (10 weeks) plus counseling. Assessments included the dopamine D2 receptor (DRD2) genotype, dopamine transporter (SLC6A3) genotype, demographic factors, and nicotine dependence. Smoking status was verified at the end of treatment (EOT) and at 6-month follow-up. The results provided evidence for a significant DRD2 × SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT, independent of treatment condition. Such effects were no longer significant at 6-month follow-up, however. These results provide the first evidence from a prospective clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A prospective evaluation of the safety and efficacy of methohexital in the emergency department

OBJECTIVE: Knowledge of a possible correlation between distal polyps found at screening sigmoidoscopy and proximal colonic lesions is important for deciding whether to perform total colonoscopy or not. PATIENTS: A prospective analysis of 2439 consecutive patients with colorectal polyps. Of these, 304 were asymptomatic subjects who underwent complete colonoscopy for screening and were found to have adenomatous or hyperplastic polyps in the distal colorectum. RESULTS: Ten (15%) out of 65 patients with distal hyperplastic polyps only and 86 (36%) out of 239 with distal adenomatous polyps were found to have adenomatous polyps in the proximal colon as well (P < 0.001). The frequency of synchronous proximal adenomas in patients with small (< or = 5 mm) or large distal adenomas (> 5 mm) was comparable (37% and 35%, respectively). However, patients with small distal adenomas had significantly smaller proximal adenomas (P = 0.004) containing less villous component (P = 0.017) than those with large distal adenomas. Neither the patient's age nor the presence of multiple distal adenomas increased the prevalence of proximal adenomas. CONCLUSION: Hyperplastic polyps found on rectosigmoidoscopy do not indicate a need for a complete colorectal examination, as 15% of patients with distal hyperplastic polyps will have proximal adenomatous polyps, a figure that is comparable with that of asymptomatic patients having no distal polyps, either hyperplastic or adenomatous. When only small distal adenomas are found at screening sigmoidoscopy in asymptomatic persons the decision to do a total colonoscopy should be based on individual considerations, as in such cases only small polyps are to be expected in the proximal colon.